title: Pharmacokinetic variability of quetiapine and the active metabolite N-desalkylquetiapine in psychiatric patients.
abstract: BACKGROUND
  Quetiapine is an atypical antipsychotic drug that was recently also approved for the treatment of uni- and bipolar depression. The antidepressive response is considered to be mediated by the metabolite N-desalkylquetiapine, and the aim of this study was to assess the interindividual pharmacokinetic variability of quetiapine and N-desalkylquetiapine in psychiatric patients based on therapeutic drug monitoring samples.
  
  
  METHODS
  Serum measurements of quetiapine and N-desalkylquetiapine performed between October 2007 and July 2008 were retrospectively included from a routine therapeutic drug monitoring database. Pharmacokinetic variability was expressed as the 5-95 percentile range in dose-adjusted serum concentrations (C/D ratios). The impact of age (65 years or older), gender, and sampling time on the C/D ratios was studied by linear mixed model analysis. Samples from patients comedicated with CYP3A4 inducers or inhibitors were examined separately.
  
  
  RESULTS
  In total, 927 serum samples from 601 patients were included (all using quetiapine immediate-release tablets). The 5-95 percentiles of the C/D ratio ranged 15-fold (0.14-2.1 nmol/L/mg) for quetiapine and fivefold (0.44-2.1 nmol/L/mg) for N-desalkylquetiapine. Elderly (65 years or older) obtained 1.5- and 1.2-fold higher C/D ratios of quetiapine (P = 0.002) and N-desalkylquetiapine (P = 0.03) compared with younger patients, respectively. Sampling time was also found to significantly affect the C/D ratios of quetiapine (P = 0.001), whereas gender was not a significant variable (P > 0.13). In three patients treated with potent CYP3A4 inducers, the observed C/D ratios of quetiapine and N-desalkylquetiapine were 77% and 11% lower than the mean C/D ratio in the study population, respectively.
  
  
  CONCLUSIONS
  The pharmacokinetic variability was greater for quetiapine compared with N-desalkylquetiapine. Age 65 years or older and comedication with CYP3A4 inducers affected the serum levels of both agents, but the relative impact was greater on quetiapine.
authors.affiliation: vCenter for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway. gryvb@farmasi.uio.no
authors.forename: Gry Vibeke
authors.initials: GV
authors.lastname: Bakken
authors.forename: Ida
authors.initials: I
authors.lastname: Rudberg
authors.forename: Espen
authors.initials: E
authors.lastname: Molden
authors.forename: Helge
authors.initials: H
authors.lastname: Refsum
authors.forename: Monica
authors.initials: M
authors.lastname: Hermann
mesh_terms: D000367:Age Factors; D014150:Antipsychotic Agents / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D003987:Dibenzothiazepines / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004347:Drug Interactions; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D006801:Humans; D000069348:Quetiapine Fumarate; D015203:Reproducibility of Results; D012189:Retrospective Studies; D012727:Sex Characteristics; D013997:Time Factors
chemical_list: D014150:Antipsychotic Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D003987:Dibenzothiazepines; D000069348:Quetiapine Fumarate; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human